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Traumatic Brain Injury: Treatment of Post-traumatic HeadachesPublished on Practical Pain Management (http://www.practicalpainmanagement.com)

Traumatic Brain Injury: Treatment of Post-traumatic

Headaches

Part 1 of this series described the biomechanics and pathophysiology of traumatic brain injuries, as

well as their symptoms: post-concussion syndrome, post-traumatic headache, and migraine. Thismonth, our author tackles treatment of TBI headaches.ByJohn Claude Krusz, PhD, MD[1]

Volume 13, Issue #5

Increased attention to traumatic brain injury (TBI) has raised renewed interest in one of itsconsequencespost-traumatic headaches (PTH). Most often these have the characteristics of migraines,migrainous headaches, and mixed tension-type headaches (TTH) and migraines, as was discussed inPart 1 of this series.1There have been a number of recent articles in medical journals that haverenewed the debate about TBI, including an article by Robbins and Conidi on sports-related injuries.

According to Seifert, there are approximately 3.8 million sports-related concussions occurring each year,

providing unique treatment challenges for medical personnel.3

The presence of new onset or persistentheadache following an injury often complicates return-to-play decisions.

The second part of this series specifically addresses the treatment of PTH and does not claim to becomprehensive. It consists of three parts: Acute treatment of post-TBI headaches using migraine-specific therapy, prophylactic therapy to suppress post-TBI headaches, and interventional treatmentsused in our outpatient headache clinic.

Acute Therapy

Quite frankly, the "classic" migraine-specific abortive medications used for treatment of acute migrainesand migrainous headachesfor example, dihydroergotamine (DHE-45) and triptansare FDA indicated

for moderate to severe migraines. A reformulated diclofenac potassium preparation (Cambia), with veryrapid absorption kinetics, is also FDA indicated for mild to moderate migraine. The spectrum of abortivemedications is covered extremely well in some of the comprehensive textbooks about headaches andmigraines, including the role of opioids.4-6A selective list of FDA-approved agents are highlighted inTable 1.

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Migraine-specific abortive therapy centers on the triptan family of compounds. Theses agents primarily

decrease neural activity in trigeminovascular afferent nerves that are sending signals from dural nerveendings to the trigeminal nucleus caudalis in the brainstem. They also have vasoconstrictive propertieson blood vessels in this system, but the main effect is on neural firing. Triptans act specifically onserotonin (5HT)-1B and 1D receptors. They should be used for disabling migraines that are moderate tosevere in intensity. If migraines are present >2 to 3 times per week, it may be wise to consider asuppressive or prophylactic medication (see next section).

Triptans can be used in conjunction with antiemetics (metoclopramide [Reglan], ondansetron [Zofran],

promethazine [Phenergan], etc), and perhaps anti-inflammatory compounds. They are indicated formoderate to severe migraines, but early intervention in the migraine process is always desirable. Someof the triptans are available in faster delivery systems like injectable and nasal spray.

Nausea should always be treated alongside the migraine. Our preference is for the prescription of themore potent antiemetics, including ondansetron or metoclopramide. In the author's practice, wesuccessfully have used these, as well as droperidol intravenously (IV) in the clinic (in small doses).

Preventative Therapy

When TBI migraines become disabling to one's lifestyle and occur more frequently than 3 times per

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week despite successful treatment with triptans or other migraine-specific therapies, it may be time to

think about suppressive or prophylactic therapy. Only four medications are FDA approved for thisindication: topiramate (Topamax), valproate sodium, propranolol, and timolol (the last of which isavailable as an optic solution primarily, and is very hard to find in tablet form). In addition, Botox iscurrently the only medication approved for prophylactic treatment of chronic migraine (Table 2).

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The first two medications were originally approved as anticonvulsants, but were found to be effective inmanaging migraine, chronic daily headaches, and cluster headaches. Sedation and cognitive side

effects, such as confusion or memory problems, however, may limit the use of topiramate. Valproatesodium has been a popular migraine preventive. The agent is usually well tolerated in the lower dosesused for headaches; however, the FDA recently issued a warning that valproate sodium can causedecreased IQ scores in children whose mothers took the medication during pregnancy. The agency nowreports that these agents are contraindicated in pregnant women for the prevention of migraineheadaches.7The -blocker propranolol is often tried as initial prophylaxis therapy. Originally, it was

noted serendipitously to help migraine headaches when it was being used for management of bloodpressure and cardiac rhythm disorders.

When we think of preventative therapy, it is wise to think about co-morbid post-concussion symptoms.This might include anxiety, depression, bipolar-like symptoms, seizures, high blood pressure, irritability,poor sleep, and mood swings. Besides these FDA-approved medications, virtually all of theanticonvulsants (we much prefer the phrase "neuronal stabilizing agents") have been tried in smalltrials, which are usually open label in nature. For example, the author published the first data onmigraine and neuropathic pain management treated with oxcarbazepine, levetiracetam, andzonisamide8-10soon after they were officially released as seizure medications. Other agents in this largegroup were also studied for migraines, chronic daily headaches, and neuropathic pain by the same

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author.11Unfortunately, in the vast majority of these studies the industry chose not to study the

medication formally in a double-blind, placebo-controlled fashion.

Similarly, many agents that are approved for other uses have been used off-label for their abilities tohelp migraine patterns. Post-TBI migraines, when accompanied by cognitive difficulties, have beenshown to respond to the treatment memantine (Namenda), officially on the market only formanagement of dementia.12,13However, many studies, primarily from Europe, have used this agent for

various pain conditions off label, and we have used it as an agent to help with cognition after TBI.14

Antidepressants, particularly the serotonin-norepinephrine reuptake inhibitors, can help depression and

anxiety, but they can also reduce pain and migraines post-TBI. The author has used venlafaxine(Effexor), duloxetine (Cymbalta), and milnacipran (Savella) off-label in his clinical practice. Medication inother categories (so-called antipsychotic agents) have also been used to suppress migraines (eg,ziprasidone) and can be very useful in post-concussion headaches accompanied by irritability, moodinstability, and sleep disorders.15

The bottom line on preventative therapy for post-TBI headaches and migraines is to look forcomorbidities that are present along with the headaches and to treat with an agent that can reduce themigraine frequency and severity and the comorbid clinical state. Off-label use of medication is perfectly

legitimate as long as the clinician explains that to the patient. We always have a patient acknowledgethis for any treatment, oral or IV, and document this in their chart and on paper.

Interventions for Refractory Migraines

Headaches and migraines that occur after a TBI can be treated in any number of ways by healthcarepractitioners. This part of the article attempts to describe more aggressive and definitive treatmentsavailable in the outpatient headache clinic setting.

The author's clinic compiled a track record in treating refractory headache and pain patients using IVmedication therapy. More than 95% of our clinic patients fared exceedingly well as far as their headacheand pain symptoms were concerned.16 We arbitrarily defined success as a greater than 50% reduction

in the headache, based on a 0 out of 10 visual analog scale (VAS) from baseline. Very few of thepatients had to be retreated. This suggested that we were not only clinically efficient but, on a costbasis, an aggressive clinic treatment of headache was less expensive than treatment in the emergencydepartment (ED) as well. It has been estimated that the direct medical costs and indirect costs, such aslost productivity, of TBI totaled an estimated $76.5 billion in the United States in 2000. 17,18

In my opinion, the ideal headache clinic would offer a large number of IV services and be staffed bynurses trained in IV therapy and monitoring with pulse oximetry. I strongly suggest that advancedcardiovascular life supporttrained staff and a crash cart with oxygen and medications are in the clinictreatment area.

I have listed all of the IV treatments to be described in the following sections in Table 3, which are based

on my clinical experience.

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Suggested IV Interventions

MgSO4

In many ways, IV magnesium sulfate (MgSO4) is sort of an "opening shot" for intractable headaches,both TBI migraines and not. It can be given alone, or combined with either antiemetics or IVcorticosteroids. There is substantial literature on the use of IV magnesium for migraines and clusterheadaches.19-22The original studies by Mauskop and colleagues studied ion-sensitive Mg++ electrodes

to measure ionized magnesium, a technique not commonly available. Magnesium has primary effects asa physiologic antagonist to calcium. It also blocks N-methyl-D-aspartic acid (NMDA)type glutamateexcitatory amino acid activity, and nitric oxide synthesis and releaseall of which are factors inmigraine pathophysiology or maintenance. In addition, magnesium augments serotonin, which may be a

direct means of blocking migraines. Multiple types of headaches, including migraines, migrainousheadaches, TTH, and cluster headaches responded to IV magnesium therapy.19The headache suffererswith the best and longest response to this treatment also had the lowest ionized Mg++ levels, both formigraines as well as for cluster headaches.20One study has summarized clinical data with IV MgSO4using doses of 0.5 to 1 g.23In general, the author uses higher doses than that, and typically uses 2.5 to3 g.21,22

Antiemetics

Antiemetics have been used along with acute opioid therapy for headaches and for pain treatment. Thisis based on the notion that the use of both agents was somehow synergistic. Animal experimentsseemed to support this idea, but human studies are not at all conclusive on this point. 24I've looked forevidence of this, but it is almost non-existent; nausea is a prominent symptom accompanyingheadache. Nevertheless, traditional ED treatment of headaches often uses a combination of opioids and

antiemetics. In the past, promethazine was the most frequently used antiemetic.25However, ourpreference is to use either ondansetron or metoclopramide, both IV and intramuscular (IM), as a firstlineantiemetic in the clinic. This is based on a study of 202 migraine patients. The study found that IVmetoclopramide 20 mg was more effective than sumatriptan 6 mg subcutaneously at reducing painintensity scores (reduction of 7.2 vs 6.2, respectively) and pain-free rates (59% vs 35%, respectively). 26

There is a growing body of evidence that a blockade of central dopamine receptor systems can enhanceanti-nociception or the pain-relieving analgesic properties of opioids.27-29One study of neuropathic pain

suggested that bupropion might decrease neuropathic pain via an effect on presynaptic reuptake ofdopamine.30These properties might explain the ability of dopamine blockers, like metoclopramide ordroperidol, to reduce migraine headachesan effect we and others have noted in the clinic setting inthe treatment of migraines.

One of the initial studies using IV droperidol used quite high doses (mean 16.6 mg) and reported nearlyall of their patients being sedated and more than 50% having extrapyramidal symptoms 24 hours aftertreatment.31We repeated the study in our clinic using from one fifth to one quarter of the dose of IVdroperidol with only 3% side effects and well over 50% success rate in reducing or eliminating refractory

migraines.32A double-blind trial of IM droperidol,33again using high doses of the medication, showed

efficacy; the placebo response rate was 57% vs 84% for droperidol. Once again, anxiety, akathisia, andsomnolence were rated as severe in 30% of patients, presumably due to the high doses employed.Thus, keeping doses quite low (around 2 mg total) can be very effective and I have quite a number ofpatients who use IM droperidol at home as rescue medication for their migraineseither with migraine-specific therapy or to avoid a trip to the ED. The starting dose is 0.625 mg of IM droperidol, repeatedafter 20 to 30 minutes, and once again if needed.

An older ED study using IM prochlorperazine compared with metoclopramide found the former to bemore reliable in reducing headache to the endpoint of the study (1 hour). Yet both groups requiredadditional rescue treatment with analgesics (57%-79%) after initial treatment with an antiemetic. 34

Another ED study compared the efficacy of IV MgSO4with prochlorperazine in acute headache patients.

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This small study (36 patients) found prochlorperazine to be statistically more effective at reducing pain

than magnesium (90% vs 56%, respectively) with fewer side effects.35One comment is that the dose ofthe MgSO4was rather low at 1 g compared to our clinic IV doses of 2 g or greater.

Ondansetron, a 5-hydroxytriptamine type 3 receptor antagonist, is a very powerful antiemetic oftenused in the management of chemotherapy-induced nausea and vomiting. The agent has been usedsuccessfully in the clinical setting as an adjunctive medication for intractable vomiting associated with

prolonged migraines (dosage: 2-4 mg IV). A search of the literature surprisingly revealed very little datato support its use in the treatment of acute or refractory migraines. Indeed, one small study involving 6children described the development of severe daily migraine-like headaches during cancer treatment.36

All patients had received daily doses of ondansetron and had a personal or family history of migraines,which may have placed them at risk of developing ondansetron-associated migraine-type headaches.The authors noted that all the children responded to stopping the medication and starting treatmentwith standard anti-migraine therapy.

Corticosteroids

There is very little literature on the use of corticosteroids to treat migraines. More data are available forthe treatment of cluster headaches, status migrainosus, or analgesic rebound headaches. 37We

frequently use dexamethasone (2-4 mg every 8-12 hours, as needed) for severe, refractory migrainesalong with IV MgSO4. Both agents are compatible in the same IV bag (unpublished observations). Otherauthors have published results from their own clinics, showing that dexamethasone was indeedeffective in their migraine and status migraine populations.38,39This is not necessarily followed by anoral taper. Long-term use of steroids has its own side effect profile.

Dihydroergotamine

Before triptans, the gold standard for treating intractable migraines was DHE, a compound similar to,but pharmacologically very different from, ergotamine. Many people forget that the pharmacologic

profile of DHE is predominantly that of a venoconstrictor, as well as a relatively mild arterial constrictor.Ergotamine is a pure arterial vasoconstrictor. Also, ergotamine is fraught with the possibility of rebound

migraines and headaches (now termed "medication overuse headache"), whereas DHE does not havethis property. DHE can be given IV or IM and has a 10- to 14-hour half-life. The original IV DHE protocolto treat refractory migraine headaches was introduced in 1986 by Professor Raskin and it became themainstay of inpatient and in-clinic treatments.40Typically, DHE (1 mg) is given every 8 hours with IVmetoclopramide 10 mg for 2 to 3 days. Comparisons of this protocol against "typical" treatment withmeperidine (75 mg) and promethazine (25 mg) showed similar efficacy with significantly fewer side

effects in the DHE/metoclopramide group,41making it very useful for office-based treatment ofmigraines. Another small study evaluated the same protocol in a headache clinic against IV ketorolacand found the DHE protocol to result in a greater degree of pain improvement (P=0.31) and betterfunction clinically (P=0.057).42Various IV protocols available for clinic use were subsequentlysummarized by the same author.43

Valproate

Divalproex sodium (Depakote), as an enteric-coated preparation, was approved in 1994 for oral use inthe prophylaxis of migraines in the United States. It was the first anticonvulsant molecule to be founduseful in treating migraines in a prophylactic manner.44-46An IV version of valproate sodium (Depacon)was developed and was used for treatment of seizures. In our search for additional IV agents to use inthe clinic for intractable migraines, we turned to this compound and presented an initial open-labelstudy in poster form.47Our results showed an impressive reduction in migraine severity, both in this

initial trial and in subsequent studies. Soon thereafter, other open-label studies, including our own,began to show up in the literature48-50documenting efficacy of valproate sodium IV in treatingmigraines.

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Our study included 85 intractable migraineurs. We reported an 88% reduction in severity of migraine,based on patient-rated VAS, in the IV valproate sodium group. The average dose of valproate was 720mg, given IV over about 50 minutes (100-200 mg every 5-10 minutes).47Another study investigated theuse of valproate sodium (loading dose 15 mg/kg, followed by 5 mg/kg every 8 hours) in initial treatmentof chronic daily headache, transformed migraine, and analgesic overuse headaches.51The authorsstated that headache improvement was reported by 80% of the patients treated with IV valproate

sodium, especially if other agents were not effective.

A third study, however, found that valproate sodium was significantly less useful than prochlorperazine

(Compazine) in the ED for headache pain (9 mm vs 64.5 mm, respectively) and nausea symptoms (35.5mm vs 2 mm, P


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lidocaine for treatment of refractory migraines and have shown some promising data. 61,62However, this

was an off-label use of lidocaine and, due to its ability to block neuropathic pain, it may play a roll in thetreatment of refractory migraine post TBI. More studies are in progress.

Ketamine

Some headache and pain physicians think that neuropathic pain, chronic daily headaches, and

migraines are, underneath it all, very similar in their biochemical underpinnings with respect to cellularmechanisms. The fields of pain and headache management use common terminologies to describethese processes. Nociceptive pain, peripheral and central sensitization, windup, long-term potentiation,and neuroplasticity are concepts basic to the expression and maintenance of these disorders. Commonneurocellular and neurotransmitter pathways may explain the clinical expression of both neuropathicpain and migraine and associated hyperalgesia and central sensitization.63On the treatment side ofthings, why is it that medications with completely different structures but similar mechanisms of action(propofol and topiramate, each of which act on GABA-A receptors) both reduce migraines, other

headaches, and pain?

Considering the evidence that excitatory amino acids like glutamate are the "bad guys" in promotingnociception in generaland hyperalgesia and possibly allodyniait is not surprising that agents, which

antagonize this system might have utility in reducing pain and headache symptoms. Compounds thatblock the NMDA sub-family of glutamate receptors either have low potency (dextromethorphan ormemantine) or they have higher potency and a narrow therapeutic index (ketamine).64

Ketamine, an agent specifically active against NMDA-type glutamate receptors in subanesthetic doses,

has been little studied thus far, but may have theoretical implications for preventing chronic migraines.One study administered ketamine intranasally to migraine patients who had pronounced and disablingaura. Fewer than 50% had successful resolution with ketamine.65In this study the dose of ketamine waslow, but more work needs to be done with this specific blocker of NMDA glutamate receptor subtypes. Aposter described increased cerebrospinal fluid glutamate levels in chronic migraineurs compared to non-migraine controls.66Patients with migraines and fibromyalgia had higher levels than patients withoutchronic pain.

Glutamate, with its subtypes of receptor families, will be an active area of research and, hopefully,treatment. As we have used IV ketamine in the clinic for more than 12 years, we have presented ourdata for IV ketamine for treating refractory headaches and pain several times.67,68This is an ongoingstudy, which includes post-TBI migraines and headaches (with and without pain) and may be the largestdatabase for migraine, cluster, chronic daily headache, and rare subtypes like paroxysmal hemicrania,hemicrania continua, and trigeminal neuralgia with migraines.69,70

Levetiracetam

Clinical data with the oral form of this neuronal stabilizing agent were the first available anywhere in thetreatment of refractory migraine headaches,71and this agent has a unique mechanism of action thateffectively blocks high-voltage calcium channelsanother major activity of many neuronal stabilizingagents.

We developed an IV form of the same agent (with a compounding pharmacy) and evaluatedlevetiracetam IV in the treatment of refractory migraines. Cluster headache flare-ups and pain flare-upslike trigeminal neuralgia and CRPS have also been treated in the clinic.72,73This is a powerful, non-toxicform of treatment for many difficult pain and headache flare-ups. The manufacturer subsequentlyreleased an IV preparation for commercial use to treat only seizures, but our data preceded thatformulation by several years. It is important to note that the author uses this preparation only inextremely refractory cases and very infrequently.

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Opioids: Tramadol

Tramadol has been available in the United States for a number of years and has been used in Europe formore than 30 years. About 2 billion people worldwide have been treated for pain with this agent, whichis a opioid receptor agonist, as well as weak presynaptic reuptake inhibition of norepinephrine andserotonin (like venlafaxine, duloxetine, or milnacipran).

I formulated a sterile IV preparation to treat headaches and pain. An IV form is available in Europe. I hadoriginally published data with the oral form of the medication in treating headaches 74and was

impressed by its ability to treat chronic headaches and migraines. The IV preparation of tramadol turnedout to be very efficacious, very well tolerated, rapidly treated refractory migraines and mixedheadaches, and gave me another tool to use in the clinic when other agents failed. 75Our most recentaccumulated data were presented this year. In our study, we treated 79 patients with IV tramadol. Theaverage dose was 423 mg (range: 250-1,100 mg), given over 95 minutes in our clinic. The resultsshowed an average reduction in pain severity after treatment from 7.46 on the visual analogue scale(VAS) to 2.81 (P


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we always have a "game plan" for the next agent. The key is to have a wide and varied repertoire of

interventions to address each unique patient's pain presentation.

Post-traumatic headaches, often considered to be extremely difficult to treat, are actually easier to treatthan most people realize if you pay attention to the parameters outlined in this article. In the future, wewill undoubtedly have more unique pharmacologic agents to treat post-TBI migraines more effectively.References:

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46. Klapper JA. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia.1997;17(2):103-108.

47. Krusz JC, Scott VB, and Belanger J. Intravenous valproate sodium in the treatment of refractorymigraine headaches. Headache Update Annual Meeting. Orlando, Florida. July 1999.

48. Mathew NT, Kailasam J, Meadors L, Chernyschev 0, Gentry P. Intravenous valproate sodium(Depacon) aborts migraine rapidly: a preliminary report. Headache. 2000;40(9):720-723.

49. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramusculardihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache.2001;41(10):976-980.

50. Krusz JC. Intravenous valproate sodium in the treatment of migraine headaches in the headacheclinic. Headache Quarterly. 2001;12:39-41.

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51. Schwartz TH, Karpitskiy VV, Sohn RS. Intravenous valproate sodium in the treatment of daily

headache. Headache. 2002;42(6):519-522.52. Tanen DA, MillerS, French T, Riffenburgh RH. Intravenous sodium valproate versus

prochlorperazine for the emergency department treatment of acute migraine headaches: aprospective, randomized, double-blind study.Ann Emerg Med. 2003;41(6):847-853.

53. Stillman MJ, Zajac D, Rybicki LA. Treatment of primary headache disorders with intravenousvalproate: initial outpatient experience. Headache. 2004;44(1):65-69.

54. Krusz JC, Cagle J, Scott V. IV valproate for status migrainosus in the headache clinic. Headacheand Pain. 2006;17:121-123.

55. Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable

migraine headaches. Headache. 2000;40(3):41-46.56. 56Krusz JC. Prophylaxis for chronic daily headache and chronic migraine with neuronal stabilizing

agents. Curr Pain Headache Rep. 2002;6(12):480-485.57. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment of

acute migraine headache.Ann Emerg Med. 1990;19(10):1079-1082.58. Reutens DC, Fatovich DM, Stewart-Wynne EG, Prentice DA. Is intravenous lidocaine clinically

effective in acute migraine? Cephalalgia. 1991;11(6):245-247.59. Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Aust.

2000;172(4):157-159.

60. Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the treatment of chronicdaily headache with substantial medication overuse. Cephalalgia. 2003;23(10):963-971.61. Krusz JC, Cagle J, Cammarata D. IV lidocaine: effective treatment for refractory migraines in the

clinic. American Headache Society 49th Annual Meeting. Chicago, Illinois. June 2007.62. Krusz JC, Cagle J. Efficacy of IV lidocaine to treat pain and headache flareups in the outpatient

clinic. American Pain Society's 27th Annual Scientific Meeting. Tampa, Florida. April 2009:Abstract 221.

63. Nicolodi M, Sicuteri F. Negative modulators of excitatory amino acids in episodic and chronic

migraine: preventing and reverting chronic migraine. Int J Clin Pharmacal Res.1998;18(2):93-100.

64. Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine: therapeutic and theoreticimplications. Int J Clin Pharmacal Res. 1995;15(5-6):181-189.

65. Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC. Aura in some patients with familialhemiplegic migraine can be stopped by intranasal ketamine. Neurology. 2000;55(1):139-141.

66. Peres MFP, Zukerman E, Soares C, Augusto S, Alonso EO, Santos BFC, Faulhaber MHW. CSFglutamate levels in chronic migraine. Cephalalgia. 2004;24:151-152.

67. Krusz JC, Cagle J, Cammarata D. IV ketamine: effective therapy in the clinic for refractory

migraines. 7th European Federation of Neurological Societies. Brussels, Belgium. August 2007.68. Krusz JC, Cammarata D, Cagle S. IV ketamine for treatment of refractory pain disorders in the

clinic. 27th Annual Scientific Meeting, American Pain Society. Tampa, Florida. May 2008.69. Krusz JC. Ketamine in an outpatient setting: effective treatment for neuropathic pain syndromes.

32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:Abstract 378.

70. Krusz JC. Ketamine IV - for CRPS, TN/TMD and other neuropathic pain in the outpatient painclinic. Fourth International Congress on Neuropathic Pain. Toronto, Canada. May 2013.


72. Krusz JC, Cagle J, Daniel D. Intravenous levetiracetam for acute intractable migraines.Cephalalgia. 2002;22:604.

73. Krusz JC, Daniel D, Cagle J. IV Levetiracetam efficacious for cluster headache. Cephalalgia.2003;23:736.

74. Krusz JC, Longmire DR. Tramadol in the treatment of headaches. American Academy of PainManagement Annual Meeting. Washington, DC. September 1996.

75. Krusz JC, Daniel D, Cagle J. IV tramadol for treating refractory migraines. 7th Congress European

Federation of Neurological Societies. Helsinki, Finland. August 2003.76. Krusz JC. IV tramadol: very efficacious treatment for pain and headache in the outpatient clinic.

Page 14 of 18


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32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:

Abstract 382.77. JC Krusz, J Cagle, D Daniel, VB Scott-Krusz. IV baclofen: treatment for refractory migraines and

daily headaches C0-morbid with muscle spasm in the outpatient clinic. 15th Congress of theInternational Headache Society. Berlin, Germany. June 2011: Abstract 15.

78. JC Krusz, J Cagle. IV baclofen for treating migraines accompanied by severe muscle spasm in anoutpatient setting. 64th Annual Meeting of the American Academy of Neurology. New Orleans,

Louisiana. April 2012: Abstract 3780.79. Krusz, JC. Baclofen IV in the clinic: effective treatment for muscle spasm pain and migraines.

32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:

Abstract 381.

View Sources[7]

1. Krusz JC, Robbins L. Traumatic brain injury. Pract Pain Manage. 2013;13(4):22-31.2. Robbins L, Conidi FX. Stop footballsave brains: a point counterpoint discussion. Headache.

2012;53(5):817-823.3. Seifert TD. Sports concussion and associated post-traumatic headache. Headache.

2013;53(5):726-736.4. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2nd edition. Oxford, UK:Martin Dunitz Ltd; 2002.

5. Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA. The Headache. 3rd edition.Philadelphia, PA: Lippincott, Williams & Wilkins; 2006.

6. Silberstein SD, Lipton RB, Dodick DW. Wolff's Headache and Other Head Pain. 8th edition.Oxford, UK: Oxford University Press; 2008.

7. FDA. FDA warns pregnant women to not use certain migraine prevention medicines.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm350866.htm. AccessedMay 6, 2013.

8. Krusz JC, Nett RB. Oxcarbazepine as migraine prophylaxis. American Headache Society AnnualMeeting. Montreal, Canada: June 2000.


10. Krusz JC. Zonisamide in the treatment of headache disorders. Cephalalgia. 2001;21:374.11. Krusz JC. Lamotrigine for chronic neuropathic pain. Eur J Neurol. 2002;9(suppl 2):185.12. Cammarata D, Krusz JC. Memantine: novel mechanism for migraine and headache prophylaxis.

47th Annual Scientific Meeting of the American Headache Society. Philadelphia, Pennsylvania:June 2005.

13. Krusz JC. Memantine for migraine and tension-type headache prophylaxis. Pract Pain Manage.2011;11(1):61-62.

14. Hopewell CA, Krusz JC, Thomson JA. Memantine for treatment of cognitive deficits after traumaticbrain injury. American Academy of Neurology Annual Meeting. Miami, Florida: April 2005.

15. Cammarata D, Krusz JC. Ziprasidone as prophylaxis for chronic daily headaches. 9th EuropeanFederation of Neurological Societies Annual Meeting. Athens, Greece: September 2005.

16. Krusz JC, Belanger J. Cost effectiveness of clinic treatment of headaches and pain. 8th WorldCongress. The Pain Clinic, Tenerife, Canary Islands. May 1998.

17. Finkelstein E, Corso P, Miller T, et al. The Incidence and Economic Burden of Injuries in the UnitedStates. New York, NY: Oxford University Press; 2006.

18. Coronado, McGuire, Faul, Sugerman, Pearson. The Epidemiology and Prevention of TBI. 2012. (inpress).

19. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate rapidly alleviatesheadaches of various types. Headache. 1996;36(3):154-160.

20. Krusz JC, Belanger J. Intravenous magnesium sulfate in the treatment of headaches. American

Academy of Pain Management Annual Meeting. Atlanta, Georgia. September 1998.21. Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines. Clin

Page 15 of 18
http://-/?-http://-/?-


16/18


17/18


48. Mathew NT, Kailasam J, Meadors L, Chernyschev 0, Gentry P. Intravenous valproate sodium

(Depacon) aborts migraine rapidly: a preliminary report. Headache. 2000;40(9):720-723.49. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular

dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache.2001;41(10):976-980.

50. Krusz JC. Intravenous valproate sodium in the treatment of migraine headaches in the headacheclinic. Headache Quarterly. 2001;12:39-41.

51. Schwartz TH, Karpitskiy VV, Sohn RS. Intravenous valproate sodium in the treatment of dailyheadache. Headache. 2002;42(6):519-522.

52. Tanen DA, MillerS, French T, Riffenburgh RH. Intravenous sodium valproate versus

prochlorperazine for the emergency department treatment of acute migraine headaches: aprospective, randomized, double-blind study.Ann Emerg Med. 2003;41(6):847-853.

53. Stillman MJ, Zajac D, Rybicki LA. Treatment of primary headache disorders with intravenousvalproate: initial outpatient experience. Headache. 2004;44(1):65-69.

54. Krusz JC, Cagle J, Scott V. IV valproate for status migrainosus in the headache clinic. Headache

and Pain. 2006;17:121-123.55. Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable

migraine headaches. Headache. 2000;40(3):41-46.56. 56Krusz JC. Prophylaxis for chronic daily headache and chronic migraine with neuronal stabilizing

agents. Curr Pain Headache Rep. 2002;6(12):480-485.57. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment ofacute migraine headache.Ann Emerg Med. 1990;19(10):1079-1082.

58. Reutens DC, Fatovich DM, Stewart-Wynne EG, Prentice DA. Is intravenous lidocaine clinicallyeffective in acute migraine? Cephalalgia. 1991;11(6):245-247.

59. Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Aust.2000;172(4):157-159.

60. Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the treatment of chronic

daily headache with substantial medication overuse. Cephalalgia. 2003;23(10):963-971.61. Krusz JC, Cagle J, Cammarata D. IV lidocaine: effective treatment for refractory migraines in the

clinic. American Headache Society 49th Annual Meeting. Chicago, Illinois. June 2007.62. Krusz JC, Cagle J. Efficacy of IV lidocaine to treat pain and headache flareups in the outpatient

clinic. American Pain Society's 27th Annual Scientific Meeting. Tampa, Florida. April 2009:Abstract 221.

63. Nicolodi M, Sicuteri F. Negative modulators of excitatory amino acids in episodic and chronicmigraine: preventing and reverting chronic migraine. Int J Clin Pharmacal Res.1998;18(2):93-100.

64. Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine: therapeutic and theoreticimplications. Int J Clin Pharmacal Res. 1995;15(5-6):181-189.

65. Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC. Aura in some patients with familialhemiplegic migraine can be stopped by intranasal ketamine. Neurology. 2000;55(1):139-141.

66. Peres MFP, Zukerman E, Soares C, Augusto S, Alonso EO, Santos BFC, Faulhaber MHW. CSFglutamate levels in chronic migraine. Cephalalgia. 2004;24:151-152.

67. Krusz JC, Cagle J, Cammarata D. IV ketamine: effective therapy in the clinic for refractorymigraines. 7th European Federation of Neurological Societies. Brussels, Belgium. August 2007.

68. Krusz JC, Cammarata D, Cagle S. IV ketamine for treatment of refractory pain disorders in theclinic. 27th Annual Scientific Meeting, American Pain Society. Tampa, Florida. May 2008.

69. Krusz JC. Ketamine in an outpatient setting: effective treatment for neuropathic pain syndromes.32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:Abstract 378.

70. Krusz JC. Ketamine IV - for CRPS, TN/TMD and other neuropathic pain in the outpatient painclinic. Fourth International Congress on Neuropathic Pain. Toronto, Canada. May 2013.


72. Krusz JC, Cagle J, Daniel D. Intravenous levetiracetam for acute intractable migraines.Cephalalgia. 2002;22:604.

Page 17 of 18


18/18


73. Krusz JC, Daniel D, Cagle J. IV Levetiracetam efficacious for cluster headache. Cephalalgia.

2003;23:736.74. Krusz JC, Longmire DR. Tramadol in the treatment of headaches. American Academy of Pain

Management Annual Meeting. Washington, DC. September 1996.75. Krusz JC, Daniel D, Cagle J. IV tramadol for treating refractory migraines. 7th Congress European

Federation of Neurological Societies. Helsinki, Finland. August 2003.76. Krusz JC. IV tramadol: very efficacious treatment for pain and headache in the outpatient clinic.

32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:Abstract 382.

77. JC Krusz, J Cagle, D Daniel, VB Scott-Krusz. IV baclofen: treatment for refractory migraines and

daily headaches C0-morbid with muscle spasm in the outpatient clinic. 15th Congress of theInternational Headache Society. Berlin, Germany. June 2011: Abstract 15.

78. JC Krusz, J Cagle. IV baclofen for treating migraines accompanied by severe muscle spasm in anoutpatient setting. 64th Annual Meeting of the American Academy of Neurology. New Orleans,Louisiana. April 2012: Abstract 3780.

79. Krusz, JC. Baclofen IV in the clinic: effective treatment for muscle spasm pain and migraines.32nd Annual Scientific Meeting of the American Pain Society. New Orleans, Louisiana. May 2013:Abstract 381.

First published on: June 1, 2013

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